Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology
Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing leptospirosis, a public health problem with global implications. Thousands of people die every year due to leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multipl...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00463/full |
| _version_ | 1811192706667380736 |
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| author | Alan John Alexander McBride Alan John Alexander McBride André Alex Grassmann Frederico Schmitt Kremer Júlia Cougo dos Santos Jéssica Dias Souza Luciano da Silva Pinto |
| author_facet | Alan John Alexander McBride Alan John Alexander McBride André Alex Grassmann Frederico Schmitt Kremer Júlia Cougo dos Santos Jéssica Dias Souza Luciano da Silva Pinto |
| author_sort | Alan John Alexander McBride |
| collection | DOAJ |
| description | Leptospira spp. are diderm (two membranes) bacteria that infect mammals causing leptospirosis, a public health problem with global implications. Thousands of people die every year due to leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) vaccine; however, success has been limited. A prospective vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to vaccine development. |
| first_indexed | 2024-04-11T23:55:52Z |
| format | Article |
| id | doaj.art-052ce688a42e49c6b70f146113bf77b4 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T23:55:52Z |
| publishDate | 2017-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-052ce688a42e49c6b70f146113bf77b42022-12-22T03:56:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-04-01810.3389/fimmu.2017.00463239599Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural VaccinologyAlan John Alexander McBride0Alan John Alexander McBride1André Alex Grassmann2Frederico Schmitt Kremer3Júlia Cougo dos Santos4Jéssica Dias Souza5Luciano da Silva Pinto6Biotechnology Unit, Technological Development Center, Federal University of Pelotas, Pelotas, Rio Grande do Sul, BrazilGonçalo Moniz Institute, Oswaldo Cruz Foundation, Ministry of Health, Salvador, Bahia, BrazilBiotechnology Unit, Technological Development Center, Federal University of Pelotas, Pelotas, Rio Grande do Sul, BrazilBiotechnology Unit, Technological Development Center, Federal University of Pelotas, Pelotas, Rio Grande do Sul, BrazilBiotechnology Unit, Technological Development Center, Federal University of Pelotas, Pelotas, Rio Grande do Sul, BrazilBiotechnology Unit, Technological Development Center, Federal University of Pelotas, Pelotas, Rio Grande do Sul, BrazilBiotechnology Unit, Technological Development Center, Federal University of Pelotas, Pelotas, Rio Grande do Sul, BrazilLeptospira spp. are diderm (two membranes) bacteria that infect mammals causing leptospirosis, a public health problem with global implications. Thousands of people die every year due to leptospirosis, especially in developing countries with tropical climates. Prophylaxis is difficult due to multiple factors, including the large number of asymptomatic hosts that transmit the bacteria, poor sanitation, increasing numbers of slum dwellers, and the lack of an effective vaccine. Several leptospiral recombinant antigens were evaluated as a replacement for the inactivated (bacterin) vaccine; however, success has been limited. A prospective vaccine candidate is likely to be a surface-related protein that can stimulate the host immune response to clear leptospires from blood and organs. In this study, a comprehensive bioinformatics approach based on reverse and structural vaccinology was applied toward the discovery of novel leptospiral vaccine candidates. The Leptospira interrogans serovar Copenhageni strain L1-130 genome was mined in silico for the enhanced identification of conserved β-barrel (βb) transmembrane proteins and outer membrane (OM) lipoproteins. Orthologs of the prospective vaccine candidates were screened in the genomes of 20 additional Leptospira spp. Three-dimensional structural models, with a high degree of confidence, were created for each of the surface-exposed proteins. Major histocompatibility complex II (MHC-II) epitopes were identified, and their locations were mapped on the structural models. A total of 18 βb transmembrane proteins and 8 OM lipoproteins were identified. These proteins were conserved among the pathogenic Leptospira spp. and were predicted to have epitopes for several variants of MHC-II receptors. A structural and functional analysis of the sequence of these surface proteins demonstrated that most βb transmembrane proteins seem to be TonB-dependent receptors associated with transportation. Other proteins identified included, e.g., TolC efflux pump proteins, a BamA-like OM component of the βb transmembrane protein assembly machinery, and the LptD-like LPS assembly protein. The structural mapping of the immunodominant epitopes identified the location of conserved, surface-exposed, immunogenic regions for each vaccine candidate. The proteins identified in this study are currently being evaluated for experimental evidence for their involvement in virulence, disease pathogenesis, and physiology, in addition to vaccine development.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00463/fullLeptospira interrogansouter membrane proteinepitope predictionbioinformaticstransport proteinsstructural modeling |
| spellingShingle | Alan John Alexander McBride Alan John Alexander McBride André Alex Grassmann Frederico Schmitt Kremer Júlia Cougo dos Santos Jéssica Dias Souza Luciano da Silva Pinto Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology Frontiers in Immunology Leptospira interrogans outer membrane protein epitope prediction bioinformatics transport proteins structural modeling |
| title | Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology |
| title_full | Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology |
| title_fullStr | Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology |
| title_full_unstemmed | Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology |
| title_short | Discovery of Novel Leptospirosis Vaccine Candidates Using Reverse and Structural Vaccinology |
| title_sort | discovery of novel leptospirosis vaccine candidates using reverse and structural vaccinology |
| topic | Leptospira interrogans outer membrane protein epitope prediction bioinformatics transport proteins structural modeling |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00463/full |
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